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Understanding the evolution of the B cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is fundamental to design the next generation of vaccines and therapeutics. We longitudinally analyze at the single-cell level almost 900 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants belong to the SH cohort. Repertoire analysis shows that the original Wuhan antigenic sin drives the convergent expansion of the same B cell germlines in vaccinated and SH cohorts. Only Omicron breakthrough infections expand previously unseen germ lines and generate broadly nAbs by restoring IGHV3-53/3-66 germ lines. Our analyses find that B cells initially expanded by the original antigenic sin continue to play a fundamental role in the evolution of the immune response toward an evolving virus., Competing Interests: Declaration of interests I.P., G.P., E.P., P.P., R.R., and E.A. are listed as inventors of full-length human mAbs described in Italian patent application nos. 102020000015754 filed on June 30, 2020, 102020000018955 filed on August 3, 2020, and 102020000029969 filed on December 4, 2020, and the international patent system no. PCT/IB2021/055755 filed on June 28, 2021. I.P., E.P., G.A., P.P., R.R., and E.A. are listed as inventors of full-length human mAbs described in the international patent system no. PCT/IB2022/061257 filed on November 22, 2022. All patents were submitted by Fondazione Toscana Life Sciences, Siena, Italy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)